This K24 Mid Career Investigator Award renewal application is focused on continued successful advances in lupus cardiovascular disease elucidation and intervention. Systemic lupus Erythematosus (SLE, lupus) is an autoimmune disease that primarily targets women between the ages of 15 and 45 years. We previously determined that myocardial nfarction rates in lupus women 35-44 yrs of age are 50 times greater than expected. The long-term goal of this project s to characterize the cardiovascular disease present in lupus women, to identify associated risk factors, and ultimately: o intervenes therapeutically. The primary goal of studies performed during the initial funding cycle was to generate critical observational data. Specifically, we determined the rate of progression of carotid intima-media thickness (IMT) and carotid plaque in a large cohort of well-defined women with lupus, representing the first observation of carotid disease progression made in lupus. We also demonstrated that lupus-related variables including organ damage, complement activation, and inflammation are associated with the presence of plaque and the progression of IMT after controlling for CV risk factors. A key observation was that immunosuppressive therapy is protective against progression of IMT, implying that more aggressive treatment of lupus results in slower vascular aging. This hypothesis is supported by our cross-sectional data that suggested that arterial stiffness is influenced by lupus disease activity, particularly in young women. This competitive renewal application is designed to extend these key observations through three Specific Aims. Specific Aim 1 is to determine the rate of progression of carotid atherosclerosis on lupus women compared to age- race- and geographically-similar controls. Specific Aim 2 is to compare qualitative differences in carotid plaque between women with lupus and healthy controls. Specific Aim 3 is to determine the association between lupus disease activity and arterial stiffness measured by aortic pulse wave velocity. We have already determined that increased serum levels of complement proteins are associated with arterial stiffening in lupus women, suggesting that the immune-mediated pathogenic mechanisms of lupus contribute to the vascular pathology. In young individuals, arterial stiffening is reversible and is a barometer for the health of the vascular system. Thus, it is likely that arterial stiffness increases during a flare of lupus disease activity and then decreases with treatment and resolution of the flare, suggesting opportunities and targets for intervention. To accomplish these aims, we will take advantage of new imaging strategies in our Ultrasound Laboratory and novel biomarkers for measuring lupus disease activity and complement activation developed at our recently created Lupus Center of Excellence. To the best of our knowledge, we have recruited and characterized one of the largest cohorts of lupus women studied for cardiovascular disease for the longest consecutive period of time. We are now uniquely positioned to make additional seminal observations regarding the progression of this pathologic process and to ultimately intervene therapeutically. This research plan will provide an ideal vehicle for training young investigators in patient-oriented research. [unreadable] [unreadable] [unreadable] [unreadable]